Received: 3 August 2021 Revised: 24 December 2021 Accepted: 9 January 2022

DOI: 10.1111/jgs.17684
Journal of the
REVIEW ARTICLE American Geriatrics Society

Time to benefit for stroke reduction after blood pressure

treatment in older adults: A meta-analysis

Vanessa S. Ho MS1,2 | Irena S. Cenzer PhD3 | Brian T. Nguyen BA3,4,5 |

2,3,4
Sei J. Lee MD, MAS

1
College of Medicine, California
Northstate University, Elk Grove,
California, USA
2
Medical Student Training in Aging
Research (MSTAR) Program, Division of
Geriatrics, School of Medicine, University
of California, San Francisco,
California, USA
3
Division of Geriatrics, School of
Medicine, University of California, San
Francisco, California, USA
4
Geriatrics, Palliative and Extended Care
Service Line, San Francisco Veterans
Affairs Medical Center, San Francisco,
California, USA
5
Northern California Institute for
Research and Education, San Francisco,
California, USA
Correspondence
Vanessa S. Ho, College of Medicine,
California Northstate University, 9700 W
Taron Dr, Elk Grove, CA 95757, USA.
Email: vanessa.ho5618@cnsu.edu
Funding information
This work is supported by the facilities
and resources of the Veterans Affairs
Medical Center, San Francisco, CA. Sei J.
Lee was also supported by grants from the
National Institute on Aging
(K24AG066998 and T35AG026736)
Abstract
Background: Hypertension treatment in older adults can decrease mortality,
cardiovascular events, including heart failure, cognitive impairment, and
stroke risk, but may also lead to harms such as syncope and falls. Guidelines
recommend targeting preventive interventions with immediate harms and del-
ayed benefits to patients whose life expectancy exceeds the intervention's time
to benefit (TTB). Our objective was to estimate a meta-analyzed TTB for stroke
prevention after initiation of more intensive hypertension treatment in adults
aged ≥65 years.
Methods: Studies were identified from two Cochrane systematic reviews and
a search of MEDLINE and Google Scholar for subsequent publications until
August 31, 2021. We abstracted data from randomized controlled trials com-
paring standard (untreated, placebo, or less intensive treatment) to more inten-
sive treatment groups in older adults (mean age ≥ 65 years). We fit Weibull
survival curves and used a random-effects model to estimate the pooled annual
absolute risk reduction (ARR) between control and intervention groups. We
applied Markov chain Monte Carlo methods to determine the time to ARR
thresholds (0.002, 0.005, and 0.01) for a first stroke.
Results: Nine trials (n = 38,779) were identified. The mean age ranged from
66 to 84 years and study follow-up times ranged from 2.0 to 5.8 years. We
determined that 1.7 (95%CI: 1.0–2.9) years were required to prevent 1 stroke
for 200 persons (ARR = 0.005) receiving more intensive hypertensive treat-
ment. Heterogeneity was found across studies, with those focusing on tighter
systolic blood pressure control (SBP < 150 mmHg) showing longer TTB. For
example, in the SPRINT study (baseline SBP = 140 mmHg, achieved
SBP = 121 mmHg), the TTB to avoid 1 stroke for 200 patients treated was
5.9 years (95%CI: 2.2–13.0).

An oral presentation based in part on the study findings was given at Plenary Paper Session at the American Geriatrics Society Annual Scientific
meeting on June 24, 2020.

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any
medium, provided the original work is properly cited and is not used for commercial purposes.
© 2022 The American Geriatrics Society. This article has been contributed to by US Government employees and their work is in the public domain in the USA.

J Am Geriatr Soc. 2022;1–11. wileyonlinelibrary.com/journal/jgs 1

2 HO ET AL.

Conclusions: More intensive hypertension treatment in 200 older adults pre-

vents 1 stroke after 1.7 years. Given the heterogeneity across studies, the TTB
estimates from individual studies may be more relevant for clinical decision-
making than our summary estimate.

KEYWORDS
hypertension, stroke, time to benefit

INTRODUCTION
Hypertension is a strong and common modifiable risk
factor for stroke. In the United States, hypertension
affects 47% adults (245 million) and 76% of older adults
≥65 years of age (48.0 million).1,2 The prevalence of
stroke is strongly age-dependent, and hypertension dra-
matically increases the risk of stroke in older adults.3,4
Data from Framingham Study suggests that hypertension
doubles the risk of stroke in older adults age 65–94, with
a relative risk (RR) of 1.9 in men and 2.3 in women.5
While hypertension treatment has been shown to reduce
stroke risk,6 it is less clear when stroke reduction occurs.
In contrast, the harms of hypertension treatment, which
include orthostatic hypotension, syncope, falls, and elec-
trolyte abnormalities, appear to occur soon after treat-
ment initiation.7–9 For example, the risk of falls and
fractures was found to be increased in the first 7–45 days
after the initiation of antihypertensive medications.10–14
Thus, while hypertension treatment decreases stroke risk
over time, it can also lead to an increased risk for adverse
effects.
For interventions with short-term potential harms
and long-term potential benefits, we previously proposed
a framework for individualizing prevention decisions that
focuses on a patient's life expectancy and an interven-
tion's time to benefit (TTB).15 Older adults with a limited
life expectancy should avoid preventive interventions
with an extended TTB, since these older adults would be
exposed to the up-front harms of the intervention with
little chance they would survive to experience the bene-
fits. Although many indexes to predict life expectancy for
older adults have been validated and are available
through websites such as ePrognosis (ePrognosis.ucsf.
edu), the TTB for hypertension treatment to prevent stro-
kes is unclear.
To help clinicians identify, which patients are most
likely to benefit from hypertension treatment (and which
patients are more likely to be harmed), our objective was
to determine the TTB of hypertension treatment for the
primary prevention of stroke. We conducted a survival
meta-analysis of major randomized clinical trials to deter-
mine the TTB for various stroke absolute risk reduction
Key points
• More intensive hypertension treatment in
200 older adults prevents 1 stroke after
1.7 years.
• For older adults with baseline systolic blood
pressures (SBP) below 150 mmHg, the time to
benefit (TTB) of more intensive hypertension
treatment appears to be substantially longer
than 1.7 years; for older adults with baseline
SBP above 190 mmHg, the TTB appears to be
shorter than 1.7 years.
Why does this paper matter?
• Since the overwhelming majority of older
adults have a life expectancy >1.7 years, our
results suggest that almost all older adults with
hypertension would benefit from treatment.
(ARR) thresholds. Specifically, we sought to quantify
how many years of hypertension treatment was necessary
before 1 stroke was prevented for 500 older adults treated
(TBB to reach an ARR of 0.002). Similarly, we sought to
quantify the TTB for ARR of 0.005 (1 stroke prevented for
200 treated) and TBB for ARR of 0.01 (1 stroke prevented
for 100 treated).
METHODS
Literature search
The Preferred Reporting Items for Systematic Review and
Meta-Analyses (PRISMA) statement guidelines were
followed (Table S1). One reviewer (VSH) identified random-
ized control trials from two systematic reviews (2017
Cochrane review entitled, “Blood pressure targets for hyper-
tension in older adults”16 and 2019 Cochrane review enti-
tled, “Pharmacotherapy for hypertension in adults 60 years
TTB FOR STROKE REDUCTION AFTER BP TREATMENT 3

FIGURE 1 Study identification and 2017 Cochrane 2019 Cochrane Review PubMed and
selection Review on Blood on Pharmacotherapy for Google Scholar
Pressure Targets Hypertension in Older search from
for Older Adults16 Adults17 01/2019 to 08/2021
(n=4) (n=16) (n=2)23,25

22 studies for full-text review

4 studies with mean age

<65 excluded

1 study focusing on
secondary prevention of
stroke excluded

2 studies with n <500

excluded

1 non-English study
excluded

5 studies without stroke

survival curves excluded

9 studies included for final analysis

or older”17). We also searched MEDLINE–PubMed and
Google Scholar for subsequently published relevant studies
up until August 31, 2021 using the search terms blood pres-
sure, hypertension, antihypertensive, older, elderly, and stroke.
The trial names, authors, and references of included trials
and published systematic reviews were screened for other
potential trials. The search strategy is detailed in Figure 1.
Since this project relied on previously published data, the
Committee on Human Research at the University of Cali-
fornia, San Francisco determined that this did not meet the
definition of human subjects research and thus did not
require review.
Eligibility criteria
prevention, we required studies to present time to
stroke data and excluded studies without stroke survival
curves.
Data extraction
We utilized previously validated methods to quantify data
from published survival curves. Specifically, we scanned
the published survival curves and used the program
DigitizeIt to reconstruct the data underlying the survival
curves.18 As a sensitivity analysis, we manually quanti-
fied the scanned survival curves from two studies and
compared the manual quantification with the DigitizeIt
program results.

This study focused on the primary prevention of stroke

in older adults. Thus, we excluded trials with a mean Outcomes of interest
age <65 years, trials focusing on secondary stroke pre-
vention, smaller studies with n < 500 and non-English Our primary outcome was time to stroke reduction after
studies. Since our outcome was the time to stroke initiation of more intensive blood pressure treatment.
4 HO ET AL.

TABLE 1 Characteristics of excluded studies

Reason(s) for exclusion

Secondary
Mean age prevention Sample Non-English No stroke
Cochrane review Studya <65 years of stroke size (n < 500) study survival curve
Garrison16 2017 JATOS26 2008 x
27
VALISH 2010 x
28
Steurer 2016 x
17
Musini 2019 Carter29 1970 x
VA-II30 1970 x X x
31
HSCSG 1974 x x
32
ATTMH 1981 x
Kuramoto33 1981 x
34
Sprackling 1981 X
35
EWPHBPE 1989 x
36
SHEP-P 1989 x
37
MRC-TMH 1992 x
HYVET P38 2003 x

Abbreviations: ATTMH, Australian therapeutic trial in mild hypertension; EWPHBPE, European working party on high blood pressure in the elderly;
HSCSG, hypertension-stroke cooperative study group; HYVET P, hypertension in the very elderly trial pilot; JATOS, Japanese trial to assess optimal systolic
blood pressure in elderly hypertensive patients; MRC-TMH, medical research council trial of treatment of mild hypertension; n, number of participants;
SHEP-P, systolic hypertension in the elderly program pilot; VA-II, Veterans administration cooperative study group on antihypertensive agents;
VALISH, Valsartan in elderly isolated systolic hypertension.
a
Studies are listed chronologically.

Statistical methodology meta-analysis was conducted in STATA 14.2. We utilized

Our statistic of interest was the “time to benefit,” which is
not routinely reported by individual studies. In order to cal-
culate the TTB for each study, we fit random-effects
Weibull survival curves using the annual event data for the
control and intervention groups, allowing both the scale
and shape Weibull parameters to vary for each arm of the
study. We then used 100,000 Markov Chain Monte Carlo
(MCMC) simulations to acquire point estimates, standard
errors, and confidence intervals for mortality rates in con-
trol and intervention arms of each study. From this model,
we obtained estimates of time to specific ARR thresholds
(ARR = 0.002, 0.005 and 0.01) for each study. Similar ARR
thresholds have been used in previously published time to
benefit analyses and risk prediction tools for shared
decision-making.19,20
Next, we pooled the estimates from each study using a
random-effects meta-analysis model. We employed the χ2
test of homogeneity and I2 statistics (with p < 0.05 and
I2 > 50%, respectively, indicating significant heterogeneity)
to determine variability in the intervention effects across
studies due to statistical heterogeneity. MCMC computa-
tions were conducted in SAS 9.4, estimates for individual
studies were obtained using R 3.4.0 and a random-effects
similar methods to estimate TTB for cancer screening in
previously published studies.21,22
RESULTS
We examined the meta-analyses conducted by the
Cochrane Collaboration in 201716 and 201917 and iden-
tified 22 studies (Figure 1). A search of Google scholar
and Medline for subsequently published studies rev-
ealed two studies, which met our inclusion criteria: 1)
a post hoc analysis23 of the SPRINT study24 and 2) the
STEP trial.25 Of the 22 studies that underwent full-text
review, 13 studies26–38 were excluded. Four studies
were excluded because the mean age of participants
was <65 years. One study focusing on secondary pre-
vention of stroke was excluded. Two studies with
n < 500 were excluded and one non-English study was
excluded. Finally, five studies did not present survival
curves or time to stroke data and were also excluded.
Two excluded studies met more than one exclusion cri-
terion (Table 1).
We identified nine randomized controlled tri-
als24,25,39–45 that met our inclusion criteria (total
TTB FOR STROKE REDUCTION AFTER BP TREATMENT 5

n = 38,779). The trials ranged in size from 724 to 9361 strokes were prevented for 100 persons treated with more
participants. The mean age in the included trials ranged intensive hypertension treatment, respectively.
from 66 to 84 years. Five of the studies were placebo- We determined that it took 3.0 years (95%CI: 1.8–4.9)
controlled studies, one study compared observation only for more intensive hypertension treatment to prevent
(no treatment) to active hypertension treatment, and 1 stroke in 100 older patients treated (ARR = 0.01;
three studies focused on standard hypertension treatment
compared to more intensive hypertension treatment.
Older trials focused on patients with a higher baseline
systolic blood pressure (SBP), resulting in a higher stroke
risk. For example, our earliest included study (Coope
198639) had a baseline SBP of 196 mmHg with a 9.5%
stroke risk in the standard treatment group. On the other
hand, our most recent included study (STEP 202125) had
a baseline SBP of 146 mmHg with a 1.7% stroke risk in
the standard treatment group. Across the studies, the
mean follow-up ranged from 2.0 to 5.8 years. The RR of
stroke reported by each individual study ranged from
0.55 to 0.89. The stroke risk in the standard treatment
group varied widely across studies, ranging from 1.5% to
10.0%. Characteristics of included studies are summa-
rized in Table 2.
Our survival meta-analysis suggested that the benefit F I G U R E 2 Meta-analyzed absolute risk reduction over time
of more intensive hypertension treatment increased with more intensive blood pressure treatment. The dark blue line
steadily with longer follow-up. (Figure 2). For example, signifies the difference in number of stroke events between
at 1 year, 0.3 strokes were prevented for 100 persons standard and more intensive blood pressure treatment groups. The
treated with more intensive hypertension treatment. At light blue areas above and below the line indicate the upper and
3 and 5 years after treatment initiation, 1.0 and 1.8 lower 95% confidence limits of the ARR, respectively

TABLE 2 Characteristics of Included Studies

Intervention Mean SBPb

Mean ΔSBP
Groups (Std Tx/Int Tx), mmHg
Age Mean achieved, Stroke Risk Stroke
Studya n (Range), y Std Tx Int Tx Baseline Achieved FU, y mmHg in Std Tx, % RR (95% CI)
39
Coope 1986 884 69 (60–79) Obs only A 196.4/196.7 180.4/162.3 4.4 18.1 9.5 0.58(0.36–0.94)
40
SHEP 1991 4736 72 (>60) P A 170.1/170.5 155.1/144.0 4.5 11.1 6.3 0.65(0.50–0.83)
STOP41 1991 1627 76 (70–84) P A 195.0/195.0 186.0/167.0 2.1 19.0 6.5 0.55(0.35–0.85)
42
MRC-O 1992 4396 70 (65–74) P A 184.7/184.7 165.0/151.6 5.8 13.5 6.1 0.76(0.58–0.97)
43 c
Syst-Eur 1997 4695 70 (>60) P A 173.9/173.8 160.9/150.8 2.0 10.1 3.4 0.58(0.41–0.84)
44
HYVET 2008 3845 84 (80–105) P A 173.0/173.0 158.3/143.5 2.1 14.8 3.5 0.74(0.52–1.05)
Wei45 2013 724 77 (>70) Std Tx Int Tx 160.3/158.8 149.7/135.7 4.0 14.0 10.0 0.58(0.35–0.97)d
SPRINT24 2015 9361 68 (>50) Std Tx Int Tx 139.7/139.7 134.6/121.4 3.3c 13.1 1.5 0.89(0.63–1.25)
25 c
STEP 2021 8511 66 (60–80) Std Tx Int Tx 146.0/146.1 135.9/126.7 3.3 9.3 1.7 0.67(0.47–0.97)

Abbreviations: ΔSBP, difference in SBP Achieved = (Intensive SBP achieved – Standard SBP achieved); A, active treatment; CI, confidence interval; FU, follow-
up; HYVET, hypertension in the very elderly trial; Int Tx, intensive treatment; MRC-O, medical research council trial of treatment of hypertension in older
adults; n, number of participants; Obs, observation; P, placebo; RR, relative risk; SBP, systolic blood pressure; SHEP, systolic hypertension in the elderly
program; SPRINT, systolic blood pressure intervention trial; Std Tx, standard treatment; STEP, strategy of blood pressure intervention in elderly hypertensive
patients; STOP, Swedish trial in old patients with hypertension; Syst-Eur, systolic hypertension in Europe; y, years.
a
Studies are listed chronologically.
b
Sitting or supine SBP.
c
Reported as median (mean follow-up years was not provided by the study).
d
Calculated by the authors of this article (CI was not provided by the study).
6 HO ET AL.
Figure 3C and Table S2). Similarly, 200 older adults
would need to receive more intensive blood pressure
treatment (ARR = 0.005; Figure 3B and Table S2) for
1.7 years (95%CI: 1.0–2.9) to prevent 1 stroke and
500 older adults would need more intensive blood pres-
sure treatment (ARR = 0.002; Figure 3A and Table S2)
for 0.9 years (95%CI: 0.5–1.7) to avoid 1 stroke.
F I G U R E 3 Forest plots for time to
benefit to achieve ARR thresholds.
(A) Forest plot for ARR = 0.002.
(B) Forest plot for ARR = 0.005.
(C) Forest plot for ARR = 0.01
We found evidence of substantial heterogeneity in TTB
across studies (Figure 3 and Table S2). For example, while
the pooled time to prevent 1 stroke per 200 persons treated
(ARR = 0.005) was 1.7 years (95%CI: 1.0–2.9), the equiva-
lent TTB for individual trials ranged from 0.7 years (95%CI:
0.2–1.8) in the STOP study to 5.9 years (95%CI: 2.2–13.0) in
the SPRINT study. For all ARR thresholds, statistical tests
TTB FOR STROKE REDUCTION AFTER BP TREATMENT
for heterogeneity indicated that the variability between indi-
vidual studies was larger than would be expected by chance
(p = 0.02 at ARR = 0.002; p = 0.01 at ARR = 0.005;
p < 0.001 at ARR = 0.01). Furthermore, I2 values ranged
from 52% at ARR = 0.002 to 72.2% at ARR = 0.01,
suggesting substantial statistical heterogeneity.46
Earlier trials with higher baseline blood pressures and
higher stroke risk appeared to have shorter times to benefit
than more recent trials with lower baseline blood pressures
and lower stroke risk. For example, the time to prevent
1 stroke per 200 persons treated was 0.7 years (95%CI:
0.2–1.8) in the STOP study (published in 1991, baseline SBP
of 195 mmHg and stroke risk of 6.5%). In contrast, the time
to prevent 1 stroke per 200 persons treated was 5.9 years
(95%CI: 2.2–13.0) in the SPRINT study (published in 2015,
baseline SBP of 140 mmHg and stroke risk of 1.5%).
DISC USS I ON
In this survival meta-analysis of 9 randomized trials of
hypertension treatment in older adults, the TTB to prevent
1 stroke per 200 older adults treated with more intensive
hypertension therapy was 1.7 years. Since the overwhelm-
ing majority of older adults have a life expectancy
>1.7 years, our results suggest that almost all older adults
with hypertension would benefit from treatment.
We found evidence of heterogeneity in TTB across
studies, with most earlier trials focusing on older adults
with higher baseline blood pressures and higher stroke
risk showing a TTB <1.7 years (for ARR threshold of
0.005) and more recent studies focusing on older adults
with lower baseline blood pressures and lower stroke risk
showing TTB >1.7 years (for ARR threshold of 0.005).
Given the clinical and statistical heterogeneity across
studies, individual patients may be best served by focus-
ing on TTB results from an individual study rather than
focusing on our pooled TTB results. For example, for
patients whose hypertension is already relatively well-
controlled with SBP near 140 mmHg and are being con-
sidered for treatment intensification to a target SBP of
120 mmHg, the SPRINT TTB results are likely to be most
relevant. For these patients, the TTB to avoid a stroke is
more likely to range from 4.0 years (ARR of 0.002) to
7.8 years (ARR of 0.01) rather than our pooled TTB esti-
mates (0.9 years for ARR = 0.002 to 3.0 years for
ARR = 0.01). On the other hand, for patients whose
hypertension is poorly controlled with an SBP over
190 mmHg, the STOP TTB results are likely to be more
relevant, with TTB to avoid stroke ranging from 0.4 years
(ARR of 0.002) to 1 year (ARR of 0.01). Thus, although
our summary TTB results provide a global estimate for
the primary prevention of stroke with antihypertensive
7
treatment, individual patients will likely be better served
by focusing on TTB results from individual studies with
participants that most closely resemble the patient.
Potential harms of antihypertensive
medications
The preponderance of evidence from observational stud-
ies, meta-analyses, and randomized trials suggests that
more intensive hypertension treatment increases the risk
for adverse events such as hypotension, syncope, and
falls.47 Leipzig and colleagues showed in a systematic
review and meta-analysis published in 1999 that while
diuretics were associated with an increased risk of falls,
the association between falls and the use of other classes
of antihypertensive medications did not reach statistical
significance.48 In a meta-analysis published in 2009,
Woolcott and colleagues updated the Leipzig study and
found that antihypertensive medications increased the
risk of falls.49 A recent meta-analysis of randomized trial
data showed that while the more intensive blood pressure
treatment did not increase the risk of falls, but did
increase the risk of hypotension and syncope.50 Taken
together, these results suggest that more intensive blood
pressure treatment can lead to hypotension, syncope, and
falls.
Recent studies have suggested that the risk of falls
and fractures is transiently increased shortly after initia-
tion and intensification of blood pressure treatment. Butt
and colleagues demonstrated that within 45 days of new
initiation of antihypertensive medications, the risk of
injurious falls requiring hospital care increased 69% and
the risk of hip fracture increased 43%.11,12 Shimbo and
colleagues found that antihypertensive medication initia-
tion and intensification was associated with an increased
risk of serious fall injury for 15 days, with attenuated
nonsignificant associations beyond 15 days.13 Berry and
colleagues showed that the risk of hip fracture increased
two-fold in the first 14 days after initiation of diuretic
antihypertensives.14 These and other studies were sum-
marized in a recent meta-analysis, which concluded that
the risk of falls is highest immediately after antihyperten-
sive medication intensification, with chronic use of anti-
hypertensive medications not being associated with
falls.10 Thus, emerging evidence suggests that antihyper-
tensive medication initiation and intensification may
result in a short-term but transiently elevated risk of falls
and fractures.
The findings from these observational studies are
supported by the SPRINT study,24 which found a border-
line increase in the number of injurious falls (defined as
life threatening or requiring an emergency room visit) in
8 HO ET AL.
the intensive versus standard treatment groups
(HR = 2.22, p = 0.05). The study also showed that inten-
sive treatment also led to increased hypotension
(HR = 2.24, p < 0.001) and syncope (HR = 2.13,
p = 0.005) compared to standard treatment. While
SPRINT focused on older hypertensive patients without
common diseases such as diabetes, stroke, and congestive
heart failure, the rates of adverse effects are expected to
be much higher in the relatively less healthy patient pop-
ulation that was excluded from the study. Consequently,
these results highlight the importance of postural blood
pressure measurements and the close monitoring of
orthostatic symptoms during initiation or intensification
of antihypertensive medications.
While hip fracture and injurious falls are clinically
important harms, falls without injury can also lead to
long-term harms. Falls and dizziness are potent risk
factors for fear of falling,51,52 which has been shown to
be associated with restriction or avoidance of daily
activities, loss of independence, reduction in social
activity, depression, and a reduction in quality of
life.53,54 Thus, while noninjurious falls are clearly less
immediately harmful than injurious falls or fractures,
they are not benign and can lead to long-term adverse
effects for older adults.
Individualizing hypertension treatment
decisions
Our results can help inform and individualize hypertension
treatment discussions. There is overwhelming evidence
that improved blood pressure control can significantly
reduce cardiovascular disease morbidity and mortality. For
most older adults, the benefit of avoiding stroke and subse-
quent permanent disability is of paramount importance.
Since these older adults place great value in avoiding
stroke, they may focus on a relatively small ARR
(i.e., ARR = 0.002) as clinically significant and choose to
initiate or continue hypertension treatment as long as their
life expectancy is >0.9 years. In contrast, other older adults
with a preexisting fear of falling may feel that the risks of
hypotension and falls are substantial. They may focus on
larger ARRs for stroke (i.e., ARR = 0.01) instead, and
choose to initiate or continue hypertension treatment as
long as their life expectancy is >3.0 years. By presenting a
spectrum of times to benefit across a range of ARRs, our
study can inform treatment discussions for older adults pri-
oritizing avoiding stroke as well as for older adults priori-
tizing avoiding hypotension and falls.
Hypertension treatment decisions need to be
informed by benefits and harms beyond stroke preven-
tion and falls. Hypertension treatment benefits beyond
stroke include decreased all-cause mortality and
decreased major adverse cardiovascular outcomes,
including heart failure and myocardial infarction, and
decreased incidence of cognitive impairment.16,17,49,55
Hypertension treatment harms beyond hypotension,
syncope, and falls include hyperkalemia and acute kid-
ney injury,49 which are usually reversible.17 For older
adults with substantial frailty or comorbidities, contex-
tual factors such as polypharmacy may also be impor-
tant considerations. Thus, individualized hypertension
treatment decisions should account for the benefits
beyond stroke prevention as well as for the risks
beyond falls and fractures.
Heterogeneity
Heterogeneity was observed to increase with larger ARR
thresholds and longer times to benefit. Specifically, at ARR
of 0.002, I2 = 52.0% (p = 0.034). The I2 value increases to
I2 = 60.1% (p = 0.01) and I2 = 72.2% (p < 0.001) at ARRs of
0.005 and 0.01, respectively. The I2 statistic estimates the
proportion of the variation in individual study results that
are due to heterogeneity rather than chance46 and an I2
value of 50% to 90% is generally considered to suggest
“moderate” to “substantial” heterogeneity.56
The observed statistical heterogeneity in our study
results is likely due to important clinical differences
between included studies (Table 2). For example, the
SPRINT study24 showed the longest times to benefit
(Figure 3 and Table S2). These findings are likely due to its
relatively modest efficacy (RR = 0.89) and low baseline risk
of stroke (1.5%). SPRINT's modest RR and low baseline risk
of stroke, and the subsequently long TTB, can be attributed
to its focus on well-controlled hypertension (mean baseline
SBP of 139.7 mmHg; target SBP <140 mmHg in standard
treatment group versus <120 mmHg in intensive treatment
group) and the active treatment of both intervention groups.
The STEP study25 also showed long times to benefit, most
likely due to lower baseline SBP (146 mmHg) and lower
baseline risk of stroke (1.7%). In general, more recent trials
(such as the SPRINT and STEP trials) focused on older
adults with lower baseline blood pressures and lower stroke
risk, resulting in longer estimates for TTB thresholds.
In contrast to SPRINT and STEP, earlier trials focused
on older adults with higher blood pressures and higher
stroke risk, resulting in shorter estimates of TTB. For
example, the STOP study41 showed the shortest TTB. This
result is most likely due to a combination of relatively
high efficacy (RR = 0.55) and higher risk of stroke (6.5%)
in participants with poorly controlled hypertension
(mean baseline SBP of 195 mmHg). In general, earlier
studies (such as STOP) focused on older adults with
TTB FOR STROKE REDUCTION AFTER BP TREATMENT
higher blood pressures and higher stroke risk, resulting
in shorter estimates of TTB.
Strength and limitations
A major strength of our study is that, to our knowledge,
this is the first study to use quantitative methods to deter-
mine the TTB for the primary prevention of stroke with
more intensive hypertension treatment in adults with a
mean age ≥ 65 years. Thus, our study fills a critical gap,
informing discussions between clinicians and patients
about when the benefits of more intensive antihyperten-
sive therapy are most likely.
One limitation is that, because SBP treatment targets
have evolved over time, there is a substantial range in
blood pressures in both the standard and intensive treat-
ment arms across the included studies. Thus, there is
clinical and methodologic heterogeneity that likely con-
tributed to the observed statistical heterogeneity.56 We
utilized random-effects meta-analysis methods, which
incorporate an assumption of underlying heterogeneity
to more flexibly account for variable treatment effects
across studies.57 When we discovered evidence of hetero-
geneity, we followed recommended best practices to
explore the potential causes of heterogeneity and found
that baseline blood pressure and baseline stroke risk to
be likely contributing factors to the observed heterogene-
ity. While heterogeneity is moderate to substantial, we
believe the fundamental similarities in our included stud-
ies (comparison of stroke rates among patients random-
ized to standard versus intensive blood pressure
treatment) allow for a meaningful pooled summary mea-
sure. However, as noted previously, evidence of heteroge-
neity suggests that for a given patient, TTB estimates
from an individual study may be more relevant than our
pooled TTB estimates.
A second potential limitation of our study is that only
the SPRINT study provided age-stratified results, preclud-
ing the presentation of age-stratified meta-analyses. Thus,
our study included participants as young as 50 years in
SPRINT and as young as 60 years in 4 other included
studies (Table 2). Since stroke risk increases almost expo-
nentially with age, it is possible that our TTB to stroke
reduction is an underestimate for the oldest patients.
Since mean ages in our included studies ranged from
64 to 84 years, our TTB estimates are likely most relevant
for older adults in this age range.
Finally, because all of our included studies focused on
primary stroke prevention after the initiation or intensifi-
cation of antihypertensive medications, it is unclear
whether our results can be extrapolated to inform de-
prescribing decisions.
9
CONCLUSIONS
In this meta-analysis, we found that 200 adults aged
≥65 years would need to be treated for 1.7 years to avoid
1 stroke. Since the overwhelming majority of older adults
have a life expectancy >1.7 years, these results suggest
that almost all older adults with hypertension would ben-
efit from treatment. We found substantial heterogeneity
across studies suggesting that for older adults with poorly
controlled hypertension (i.e., SBP >190 mmHg), the TTB
to prevent 1 stroke for 200 persons treated is likely sub-
stantially shorter than 1.7 years. Conversely, for older
adults with relatively well-controlled hypertension
(i.e., SBP <150 mmHg), the TTB to prevent 1 stroke for
200 persons treated is likely substantially longer than
1.7 years.
CONFLICT OF INTEREST
The author declares that there is no conflict of interest.
AUTHOR CONTRIBUTIONS
All authors have read and approved the submission of this
manuscript. Vanessa S. Ho and Sei J. Lee conceived the
study and designed the protocol. Vanessa S. Ho performed
the literature search, selected the studies, and extracted
the survival data, which was reviewed by Sei J. Lee.
Vanessa S. Ho, Irena S. Cenzer, Brian T. Nguyen, and Sei
J. Lee synthesized the data. Vanessa S. Ho wrote the first
draft of the article. All authors critically revised successive
drafts of the article and approved the final version. Sei
J. Lee obtained funding. Vanessa S. Ho and Sei J. Lee are
the study co-guarantors. All authors had full access to all
of the data in the study and take responsibility for the
integrity of the data and the accuracy of the data analysis.
SP ONS O R 'S RO LE
The funders had no role in the design and conduct of the
study; collection, management, analysis, and interpreta-
tion of the data; preparation, review, or approval of the
manuscript; and decision to submit the manuscript for
publication.
ORCID
Vanessa S. Ho https://orcid.org/0000-0003-3982-4616
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SU PP O R TI N G I N F O RMA TI O N
Additional supporting information may be found in the
online version of the article at the publisher's website.
Table S1. Preferred Reporting Items for Systematic
Reviews and Meta-Analyses (PRISMA) 2020 Checklist
and PRISMA 2020 for Abstracts Checklist.
Table S2. Time to Benefit for the Primary Prevention of
Stroke for Older Adults Treated with More Intensive
Hypertension Treatment.
How to cite this article: Ho VS, Cenzer IS,
Nguyen BT, Lee SJ. Time to benefit for stroke
reduction after blood pressure treatment in older
adults: A meta-analysis. J Am Geriatr Soc. 2022;
1-11. doi:10.1111/jgs.17684